The present invention relates to uniform polymer particles, a process for preparing the uniform polymer particles, an apparatus suitable for use in the process and a method of direct extracorporeal hemo-perfusion treatment using the uniform polymer particles. More particularly, the present invention relates to uniform polymer particles which can be widely used, for instance, as a parent material for an ion exchange resin, as a packing for a chromatograph, as a support onto which an enzyme is immobilized, as a support for an affinity chromatograph, as a material for a foamed article, and the like; to a process for preparing the uniform polymer particles; to an apparatus for forming uniform liquid droplets by jetting a liquid with a high viscosity, containing a natural high molecular substance or a synthetic high molecular substance, from an orifice at a constant flow rate while applying cyclic turbulences having a constant frequency thereto; and to a method of direct extracorporeal hemo-perfusion treatment using the uniform polymer particles.
As methods for preparing polymer particles in a spherical form, there have been hitherto known dispersion methods and spray methods.
According to a dispersion method, polymer particles are obtained by coagulating a dilute polymer solution containing a pore-forming agent being dispersed in the form of droplets in a dispersion medium containing a surface active agent, through volatilizing the solvent thereof [cf. Japanese Unexamined Patent Publication (Tokkyo Kokai) No. 24430/1981], or through gradually adding a coagulating agent for the droplets [cf. Japanese Unexamined Patent Publication (Tokkyo Kokai) No. 159801/1982]. However, in the dispersion method, no polymer particles other than polymer particles with a broad particle size distribution can be obtained. Also, in the dispersion method, in order to remove the solvent, the dispersion medium and the surface active agent from the coagulated particles, it is necessary to wash the coagulated particles not only with water but also with an organic solvent.
There is known another dispersion method in which polymer particles are obtained by polymerizing polymerizable monomers after dispersing the monomers in a dispersion medium, the polymer particles thereby obtained also have a broad particle size distribution. In observing the particles by an electron microscope, there can be found that minute spherical particles aggregate to form a particle. When a suspension of the above-obtained particles is stirred by a magnetic stirrer, minute polymer chips occur in a large amount, which is presumed to be due to the above-described structure of the particles. Further, the particles obtained by the above method have pores with a broad pore size distribution. Especially, on the particle surface, the particles have various size of openings.
According to a spray method, polymer particles is obtained by spraying a polymer solution into a coagulating liquid. Thus obtained polymer particles also have a broad particle size distribution and the particles have relatively large particle size [cf. Japanese Unexamined Patent Publication (Tokkyo Kokai) No. 129788/1977].
Polymer particles with a broad particle size distribution require a further process of classification. As generally known, by a classifying process, for instance, a sieving process, it is possible to make not less than 80% by volume of the whole particles have a particle size within the range of .+-.20% of the volume average particle size. In the sieving process, it is also possible to remove particles with a particle size of not less than the size of sieve opening by the sieve. However, in order to pass all of the particles with a particle size of less than the size of sieve opening, a long time sieving is necessary. Further, using the sieving process results in a very low yield. Therefore, it is not industrially practical to use such a process. Particularly, it is practically very difficult or virtually impossible to remove all of particles having a particle size of not more than 5% of the volume average particle size.
When very small particles or very large particles are included in the polymer particles, various problems arise in uses of the particles. For instance, when the particles are used as a packing for chromatography or an adsorbent, the very small particles are mixed in the liquid to be treated, or cause a large pressure drop, and the very large particles cause a lowering of the separation efficiency or the adsorption rate.
When particles having pores with a broad pore size distribution, particularly openings on the particle surface with a broad opening size distribution, are used as an adsorbent, such particles cause an inferior physical selectivity.
Recently, there has been found a technique for forming uniform liquid droplets, in which cyclic turbulences are applied to a liquid jetted at a constant flow rate (hereinafter such technique referred to as "vibration method").
There has been already reported that uniform particles are obtained by applying the above technique to the dispersion method using polymerizable monomers [cf. Japanese Unexamined Patent Publication (Tokkyo Kokai) 102905/1982]. However, the particles thus obtained have the above-stated structure, i.e. minute particles coagulate to form a particle, and therefore the particles have defects in that polymer chips easily occur and that the particles have pores with a broad pore size distribution.
There are reported some examples of polymer particles or capsules that are prepared by applying the vibration method [cf. Japanese Unexamined Patent Publication (Tokkyo Kokai) No. 129686/1977 and Japanese Unexamined Patent Publication (Tokkyo Kokai) No. 112833/1984]. However, in an example disclosed in Japanese Unexamined Patent Publication No. 129686/1977, a very dilute polymer solution, i.e. a solution with a very low viscosity is employed and micro-capsules are prepared in another example disclosed in Japanese Unexamined Patent Publication No. 112833/1984, and particles with a large particle size are prepared since nozzles themselves are directly vibrated and therefore the vibration frequency is restricted to a low frequency. In both examples, it is necessary that a multiple tubular nozzle is employed and more than one kinds of solutions are simultaneously jetted with keeping a delicate balance.
Also, in Japanese Examined Patent Publication (Tokkyo Kokoku) No. 33134/1981, there is disclosed that the vibration method is applied to a process for preparing uniform particles of an inorganic compound. In this or other publications, cyclic turbulences of flow rate of the liquid jetted from an orifice of a nozzle are applied by applying vibrational energy to the whole nozzle part.
Generally, the force F (dyn) required to vibrate an object with a mass M (g) at a frequency f (Hz) with an amplitude 2D (cm) is calculated by the following equation: EQU F=M.multidot.(2.pi.f).sup.2 .multidot.D
For instance, when the total vibrating mass of nozzle and vibration transmission part is 1,000 g, the frequency is 10,000 Hz and the amplitude is 10 .mu.m, F is about 2.times.10.sup.9 dyn. In order to stably generate the above vibration by an electromagnetic coil vibrator, there is required an electric power as enormous as several tens of KVA. Therefore, it is not economical to directly vibrate the nozzles, particularly when a high frequency of vibration is required.
In Japanese Unexamined Patent Publication (Tokkyo Kokai) No. 83202/1986, it is disclosed that the vibration method is applied to form uniform liquid droplets of polymerizable monomers. In this case, such enormous energy as in the previous case is not required since the vibration is directly transmitted to the polymerizable monomers by a piezoelectric vibrator which itself constitutes a part of the vessel containing the monomers which are jetted through the orifices. However, when employing a high viscosity liquid such as a polymer solution, not a low viscosity liquid such as a polymerizable monomer, it is supposed that a high pressure is imposed on the piezoelectric vibrator and therefore the vibrator is destroyed or the vibrator does not generated a stable vibration. Also, there is the possibility that the vibrator does not vibrate a stable vibration when the liquid is heated in order to reduce the viscosity.
W. E. Yates and his co-worker developed an apparatus for preparing uniform liquid droplets using a magnetostrictive vibrator as a vibration generator. [cf. W. E. Yates and N. B. Akesson, Proceedings of the 1st International Conference on Liquid Atomization and Spary Systems (Proc. ICLASS), 181-185 and 459 to 460 (1978)]. In the above apparatus, the vibration transmission part is embedded in a fixing cylinder with a potting agent, and at the end thereof is fixed to a vibrating rod. As well known by a person skilled in the art, the vibration transmission part is precisely designed so as to resonate with the vibration generated by the magnetostrictive vibrator and so as to have a function of amplifying its small amplitude of vibration. The vibrating rod is also precisely designed so that the amplitude reaches its maximum at the end of the rod by resonating with the vibration generated by the magnetostrictive vibrator. Therefore, when the vibration-transmission part is heated or subjected to an external force, a constant vibration can not be obtained, since the vibration transmission part or the vibrating rod does not resonate with the magnetostrictive vibrator. In the apparatus of W. E. Yates et al., it is not possible to keep the temperature of the vibration transmission part constant and to restrict external force being applied only to the end of vibrating rod. Therefore, it is presumed that it is not possible to form uniform liquid droplets from a high temperature liquid or a high pressure liquid by the apparatus of W. E. Yates et al.
Various conditions for preparing uniform liquid droplets by the vibration method have been studied in detail as disclosed by T. Sakai [cf. T. Sakai, Proc. ICLASS-'82, 37 to 45 (1982)]. It has been found that when uniform liquid droplets are stably formed, parameters including a viscosity and a surface tension of the liquid, a flow rate of liquid jetted from the orifice, a size of the orifice, and a frequency and a displacement of cyclic turbulences are within a specific range is (hereinafter, such specific range is referred to as "synchronized condition"). As a general tendency, the higher the liquid viscosity becomes and the smaller the size of the orifice becomes, the higher flow rate and frequency of jetted liquid are required to be synchronized. That is, in order to form liquid droplets with a small diameter from a liquid containing high molecular substances, the aperture diameter of the orifice must be small, and the flow rate and frequency of jetted liquid must be high. In addition, in many cases, such liquid has a high temperature and a high pressure. Consequently, it is difficult to form uniform liquid droplets with a small particle size from such liquid by applying the conventional methods.
In recent years, there has been tried an extracorporeal hemo-perfusion treatment using an adsorbent, for various obstinate diseases and its effect has been confirmed. As generally known, blood cells are physiologically quite unstable outside of the body, and therefore easily injured. For instance, there occurs a decrease in their number because of their adhesion to the matters with which blood cells contact, e.g. by hemolysis or coagulation. Therefore, in an extracorporeal hemo-perfusion treatment, blood is separated into unstable blood cells and relatively stable blood plasma by a centrifugal separator or by a membrane for the separation of blood plasma, and then the blood plasma containing pathogenic substances is treated by an adsorbent. However, it is known as a matter of course that if blood can be treated directly by an adsorbent, not only the extracorporeal hemo-perfusion treatment system can be remarkably simplified but also physiological burden to the patient can be alleviated.
As for the relationship between blood compatibility and adsorbent characteristics, in other words, whether an adsorbent injures blood or not, though there are many points not explicated chemically, there has been physically explicated a point that in order not to injure blood, an adsorbent should be smooth on its surface and the pressure drop occured in using it should be small.
A granular activated charcoal adsorbent has been employed in a direct extracorporeal hemo-perfusion system since decades ago [cf. T. M. S. Chang et al, Trans Amer. Soc. Artif. Int. Organs 17, 246 (1971)]. At the beginning, an adsorbent covered with a hydrophilic polymer was employed for the purpose of avoiding the effluence of activated charcoal and improving the chemical blood compatibility. Recently, uncovered activated charcoal with smooth surface has been employed [cf. V. Bonomini and T. M. S. Chang, "Hemoperfusion" (1981), ISBN 3-8055-3421-3]. This fact shows that the relationship between blood compatibility and chemical characteristics of adsorbent is hard to estimate since the chemical properties of the surface of the above two adsorbents are quite different. The granular activated charcoal has a relatively large average particle size of 0.5 to 3 mm. The granular activated charcoal adsorbent is employed with the object of adsorbing blood plasma components having a relatively low molecular weight. Such components can be rapidly adsorbed even if the granular activated charcoal has a large particle size. However, pathogenic substances causing obstinate diseases are, in many cases, substances having a high molecular weight of several hundreds of thousand to several millions daltons. Since such substances having a high molecular weight diffuse at a low rate, it is required that particles for an adsorbent for such substances have a particle size of not more than about 400 .mu.m, preferably not more than 300 .mu.m so as to attain a practical adsorption rate. However, there has not been hitherto well known an example of carring out a direct extracorporeal hemo-perfusion treatment using granular activated charcoal adsorbent having such a small particle size. Though there is a report in which a direct extracorporeal hemo-perfusion treatment is carried out using a modified polyvinyl alcohol gel having particle sizes of 74 to 210 .mu.m [cf. Ichikawa et al, Jinkozoki 12 (1), 116 (1983)], there are not reported data showing whether a hemolysis occurs or not and data of pressure drop, these data being basic data relating to blood compatibility.
As described above, in prior arts, there are defects that the polymer particles have a broad particle size distribution or that minute polymer chips occur due to the particle structure, and further that in preparing such polymer particles, such a complicated apparatus as a multiple tubular nozzle is necessary and a delicate operation is required.
In a conventional apparatus for forming liquid droplets, it is difficult to form uniform liquid droplets having a small particle size from a high viscosity liquid. Further, when the liquid has a high temperature and a high pressure, it is still more difficult to form uniform liquid droplets with a conventional apparatus.
An object of the present invention is to provide uniform particles having a structure which does not cause an occurence of minute polymer chips and a process for preparing such particles.
A further object of the present invention is to provide an apparatus suitable for use in the above process, which can form uniform liquid droplets from a liquid even if the liquid has not only a high viscosity but also a high temperature and a high pressure.
As described above, through there has not been explicated what chemical properties an adsorbent should have so that a direct extracorporeal hemo-perfusion treatment can be carried out employing the adsorbent, at least, the pressure drop occured in using it should be small, and the surface of the adsorbent should be smooth. Further, it has not been clear what properties of the adsorbent are suitable for evaluating blood compatibility therewith since conventional adsorbents have a broad particle size distribution. As described above, there are many points not explicated chemically as to the relationship between blood compatibility and the properties of the adsorbent.
A still further object of the present invention is to provide a method of direct extracorporeal hemo-perfusion treatment using uniform polymer particles with a practical flow rate of blood to be treated without causing problems such as hemolysis and increase in pressure drop.